The present invention relates to pharmaceutical compositions useful for treatment of inflammation in humans utilizing compounds that are prodrugs of 6-methoxy-2-naphthylacetic acid (hereinafter xe2x80x9c6MNAxe2x80x9d).
Various naphthalene derivatives are known to be useful for the treatment of inflammation and for various rheumatic and arthritic conditions. For example, Naproxen having the formula (I): 
as described in U.S. Pat. No. 4,009,197 to Fried et al. Compound (I) can, however, cause severe irritation of the gastrointestinal tract at dosages only slightly greater than the excess of the therapeutic dose.
Another naphthalene derivative is nabumetone having the formula (II): 
as described in U.S. Pat. Nos. 4,061,779 and 4,420,639 to Lake et al. Nabumetone works by inhibiting cyclooxygenase, an enzyme responsible for making prostaglandins which are mediators of inflammation. Nabumetone is a prodrug which undergoes hepatic biotransformation to the active component, 6-methoxy-2-naphthylacetic acid, Formula (III): 
(See Haddock, R. E. et al; Metabolism of Nabumetone (BRL 14777 by various species including man,xe2x80x9d Xenobiotica; 14(4): 327-337 (1984)). Nabumetone is commercially available as Relafen(copyright) from Smithkline Beecham, Inc. However, only about 35 percent of orally administered nabumetone is transferred in vivo into 6MNA.
It is therefore an object of the present invention to provide 6MNA prodrugs which are more readily transformed into 6MNA than nabumetone. It is believed that improvement in the body""s ability to hydrolyze and solubilize the prodrug can contribute to this transformation. Thus, it is another object to improve the hydrolysis and solubility of the prodrug to provide better transformation to 6MNA.
Another concern with 6MNA and its related prodrugs is that the presence of the carboxylic acid moiety can cause stomach irritation and/or ulceration. Thus, it is another object of the present invention that provides prodrugs of 6MNA having a reduced propensity to cause stomach irritation.
The present invention provides compositions useful for the treatment of inflammation in humans, and related methods of treatment for the same. In one embodiment the composition is: 
wherein R is selected from the group consisting of (CH2)mO(CH2)n; (CH2)m(OC2H4)pO(CH2)n; (CH2)m(CHOH)r(CHOH)s, and the (R) and (S) enantiomers, and mixtures thereof, and CH2CORxe2x80x2; wherein m is an integer from 2 to 4, n and p are integers from 1 to 4 and r and s are integers from 1 to 2, and Rxe2x80x2 is selected from the group consisting of C1 to C6 alkyl, (CH2)mO(CH2)n, CH2 (OC2H4)pO(CH2)n, and CH2 (OC2H4)p. Noting that as recognized by one skilled in the art that when an alkyl group is defined as xe2x80x9c(CH2)nxe2x80x9d, the actual structure will be (CH2)nxe2x88x921CH3. In another embodiment, R is selected from the group consisting of (CH2)aC(O)Rxe2x80x2 wherein Rxe2x80x2 is selected from the group consisting of C1 to C6 alkyl and hydroxy, (OC2H4)bCH3, (OC2H4)c(CH2)dCH3, (OC2H4)eONO2, (CH2)fO(CH2)gONO2 and wherein a is an integer from 0 to 4, b, c, d, e and f individually are integers from 1 to 5 and g is an integer from 2 to 5.
In yet another embodiment, the composition is a pharmaceutical composition useful for treatment of inflammation in humans comprising a therapeutically effective amount of a compound of the formula: 
wherein X is 0 or N, n is from 0 to 5 and R is xe2x80x94OCH3 or xe2x80x94ONO2.
In still another embodiment of the present invention, the composition is a pharmaceutical composition useful for treatment of inflammation in humans comprising a therapeutically effective amount of a compound of the formula: 
wherein Rxe2x80x3 is selected from the group consisting of C1 to C6 alkyl, CH2 (OC2H4)nO(CH2)n, CH2(OC2H4)pOCH3, (OC2H4)nONO2, (OC2H4)nO(CH2)n, (CH2)n(OC2H4)mONO2, (OC2H4)nO(CH2)mOH, NH(CH2)m(OC2H4)n, NH(CH2)m(OC2H4)mONO2, NHO(CH2)nCH3, NH(CH2)m(OC2H4)pOCH3, and NH(OC2H4)pOCH3, wherein m is an integer from 0 to 4, and n and p are integers from 1 to 4 noting as recognized by one skilled in the art that when an alkyl group is defined as xe2x80x9c(CH2)n, the actual structure will be (CH2)nxe2x88x921CH3. Alternately Rxe2x80x3 is selected from the group consisting of NH(CH2)aOCH3, NH(CH2)aO(CH2)bCH3, NHOCH3, NH(CH2CH2O)cCH3, NHO(CH2)dCH3, NH(CH2CH2O)c(CH2)eCH3 and NH(CH2CH2O)cH wherein a is an integer from 2 to 4 and b, c, d and e are individually integers from 1 to 4.
In yet another embodiment, the composition is 
wherein Rxe2x80x2xe2x80x3 is selected from the group consisting of hydrogen, O(CH2)nCH3, C1 to C6 alkyl, (CH2)m(OC2H4)pO(CH2)p, (CH2)m(OC2H4)p, (CH2)m(OC2H4)nONO2, (CH2)m(OC2H4)pO(CH2)mOH, and (CH2)mNHO(CH2)nCH3 wherein m is an integer from 2 to 4, and n and p are integers from 1 to 4 noting as recognized by one skilled in the art that when an alkyl group is defined as xe2x80x9c(CH2)nxe2x80x9d, the actual structure will be (CH2)nxe2x88x921CH3. In another embodiment, Rxe2x80x2xe2x80x3 is selected from the group consisting of hydroxy, O(CH2)aCH3, (CH2)bOCH3, (CH2)bO(CH2)cCH3, (OC2H4)dH, CH2COO(CH2)eCH3, CH2COOH, CH2COOCH3 and (CH2)fO(CH2)gONO2 and wherein a is an integer from 0 to 4, b, f and g are integers from 2 to 4 and c, d and e are integers from 1 to 4.
Additional alternative embodiments are R or Rxe2x80x3 are therapeutic moieties. In another embodiment optionally there may be linking groups G connecting the therapeutic moiety to the end group.
The compositions summarized above can be used in methods of treating inflammation.